The present invention relates to bicyclic heterocycles of general formula 
the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
In the above general formula I
X denotes a methyne group substituted by a cyano group or a nitrogen atom,
Ra denotes a hydrogen atom or a methyl group,
Rb denotes a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus in each case is substituted by the groups R1 to R3, where
R1 and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
a methyl, ethyl, hydroxy, methoxy, ethoxy, amino, cyano, vinyl or ethynyl group,
an aryl, aryloxy, arylmethyl or arylmethoxy group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms or
R1 together with R2, if they are bound to adjacent carbon atoms, denotes a xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CH, xe2x80x94CHxe2x95x90CHxe2x80x94NH or xe2x80x94CHxe2x95x90Nxe2x80x94NH group and
R3 denotes a hydrogen, fluorine, chlorine or bromine atom,
one of the groups Rc or Rd denotes an xe2x80x94Axe2x80x94B group and
the other group Rc or Rd denotes a xe2x80x94Cxe2x80x94D group, where
A denotes a C1-6-alkylene group, a xe2x80x94Oxe2x80x94C1-6-alkylene group, where the alkylene moiety is linked to the group B, or an oxygen atom, while this may not be linked to a nitrogen atom of the group B, and
B denotes a pyrrolidino group wherein the two hydrogen atoms in the 2 position are replaced by a group E, wherein
E represents a xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CO, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2 or xe2x80x94CH2CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups,
a pyrrolidino group wherein the two hydrogen atoms in the 3 position are replaced by a group F wherein
F denotes an xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CO, xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2, xe2x80x94CH2CH2CH2xe2x80x94Oxe2x80x94CO, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NR4xe2x80x94CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NR4, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94CH2 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups, where R4 denotes a hydrogen atom or a C1-4-alkyl group,
a piperidino or hexahydroazepino group, wherein the two hydrogen atoms in the 2 position are replaced by a group E, where E is as hereinbefore defined,
a piperidino or hexahydroazepino group, wherein in each case the two hydrogen atoms in the 3 position or in the 4 position are replaced by a group F, where F is as hereinbefore defined,
a piperazino or 4-(C1-4-alkyl)-piperazino group, wherein the two hydrogen atoms in the 2 position or in the 3 position of the piperazino ring are replaced by a group E, where E is as hereinbefore defined,
a pyrrolidino or piperidino group, wherein two neighbouring hydrogen atoms are replaced by a xe2x80x94Oxe2x80x94COxe2x80x94CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94CO, xe2x80x94Oxe2x80x94COxe2x80x94CH2CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CO, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NR4 or xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups, where
R4 is as hereinbefore defined and the heteroatoms of the abovementioned bridges are not bound to the 2 or 5 position of the pyrrolidino ring and are not bound to the 2 or 6 position of the piperidino ring,
a piperazino or 4-(C1-4-alkyl)-piperazino group, wherein a hydrogen atom in the 2 position together with a hydrogen atom in the 3 position of the piperazino ring are replaced by a xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2 or xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups,
a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a xe2x80x94COxe2x80x94Oxe2x80x94CH2CH2 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups, where in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring,
a pyrrolidino, piperidino or hexahydroazepino group substituted by the group R5 wherein
R5 represents a 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1,4-dioxanyl or 2-oxo-4-(C1-4-alkyl)-morpholinyl group optionally substituted by one or two C1-2-alkyl groups,
a pyrrolidino group substituted in the 3 position by a 2-oxo-morpholino group, while the 2-oxo-morpholino group may be substituted by one or two C1-2-alkyl groups,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a 2-oxo-morpholino group, while the 2-oxo-morpholino group may be substituted by one or two C1-2-alkyl groups,
a 4-(C1-4-alkyl)-piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by R5, wherein R5 is as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4 position by the group R6, wherein
R6 represents a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group optionally substituted by one or two C1-2-alkyl groups,
a pyrrolidino group substituted in the 3 position by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, where R4 and R6 are as hereinbefore defined,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by an (R4NR6), (R6O, R6S, R6SO or R6SO2 group, wherein R4 and R6 are as hereinbefore defined,
a pyrrolidino, piperidino or hexahydroazepino group substituted by an R5xe2x80x94C1-4-alkyl, R4NR6)xe2x80x94C1-4-alkyl, R6Oxe2x80x94C1-4-alkyl, R6Sxe2x80x94C1-4-alkyl, R6SOxe2x80x94C1-4-alkyl, R6SO2xe2x80x94C1-4-alkyl or R4NR6xe2x80x94CO group, wherein R4 to R6 are as hereinbefore defined,
a pyrrolidino group substituted in the 3 position by an R5xe2x80x94COxe2x80x94NR4, R5xe2x80x94C1-4-alkylene-CONR4, (R4NR6)xe2x80x94C1-4-alkylene-CONR4, R6Oxe2x80x94C1-4-alkylene-CONR4, R6Sxe2x80x94C1-4-alkylene-CONR4, R6SOxe2x80x94C1-4-alkylene-CONR4, R6SO2xe2x80x94C1-4-alkylene-CONR4, 2-oxo-morpholino-C1-4-alkylene-CONR4, R5xe2x80x94C1-4-alkylene-Y or C2-4-alkyl-Y group, where the C2-4-alkyl moiety of the C2-4-alkyl-Y group in each case is substituted from position 2 by an (R4NR6), R6O, R6S, R6SO or R6SO2 group and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups, wherein
R4 to R6 are as hereinbefore defined and
Y represents an oxygen or sulphur atom, an imino, Nxe2x80x94(C1-4-alkyl)-imino, sulphinyl or sulphonyl group,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by an R5xe2x80x94COxe2x80x94NR4, R5xe2x80x94C1-4-alkylene-CONR4, (R4NR6)xe2x80x94C1-4-alkylene-CONR4, R6Oxe2x80x94C1-4-alkylene-CONR4, R6Sxe2x80x94C1-4-alkylene-CONR4, R6SOxe2x80x94C1-4-alkylene-CONR4, R6SO2xe2x80x94C1-4-alkylene-CONR4, 2-oxo-morpholino-C1-4-alkylene-CONR4, R5xe2x80x94C1-4-alkylene-Y or C2-4-alkyl-Y group, wherein
Y is as hereinbefore defined, the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, where R4 to R6 are as hereinbefore defined,
a 4-(C1-4-alkyl)-piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by an R5xe2x80x94C1-4-alkyl, (R4NR6)xe2x80x94C1-4-alkyl, R6Oxe2x80x94C1-4-alkyl, R6Sxe2x80x94C1-4-alkyl, R6SOxe2x80x94C1-4-alkyl, R6SO2xe2x80x94C1-4-alkyl or R4NR6xe2x80x94CO group, wherein R4 to R6 are as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4 position by an R5xe2x80x94C1-4-alkyl, R5xe2x80x94CO, R5xe2x80x94C1-4-alkylene-CO, (R4NR6)xe2x80x94C1-4-alkylene-CO, R6Oxe2x80x94C1-4-alkylene-CO, R6Sxe2x80x94C1-4-alkylene-CO, R6SOxe2x80x94C1-4-alkylene-CO or R6SO2xe2x80x94C1-4-alkylene-CO group, wherein R4 to R6 are as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4 position by a C2-4-alkyl group, wherein the C2-4-alkyl group is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO or R6SO2 group, where R4 and R6 are as hereinbefore defined,
a pyrrolidino, piperidino or hexahydroazepino group substituted by a 2-oxo-morpholino-C1-4-alkyl group, wherein the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups,
a pyrrolidino group substituted in the 3 position by a C2-4-alkyl-Y group, wherein
Y is as hereinbefore defined and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a 2-oxo-morpholino group optionally substituted by one or two C1-2-alkyl groups,
a piperidino or hexahydroazepino group substituted in the 3 or 4 position by a C2-4-alkyl-Y group, wherein
Y is as hereinbefore defined and the C2-4-alkyl moiety of the C2-4-alkyl-Y group is substituted in each case from position 2 by a 2-oxo-morpholino group optionally substituted by one or two C1-2-alkyl groups,
a 4-(C1-4-alkyl)-piperazino or 4-(C1-4-alkyl)-homopiperazino group substituted at a cyclic carbon atom by a 2-oxo-morpholino-C1-4-alkyl group, wherein the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups,
a piperazino or homopiperazino group substituted in the 4 position by a 2-oxo-morpholino-C1-4-alkylene-CO group, wherein the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups,
a piperazino or homopiperazino group substituted in the 4 position by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by a 2-oxo-morpholino group optionally substituted by one or two C1-2-alkyl groups,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by the group R6, by an R5xe2x80x94C1-4-alkyl, R5xe2x80x94CO, R5xe2x80x94C1-4-alkylene-CO, (R4NR6)xe2x80x94C1-4-alkylene-CO, R6Oxe2x80x94C1-4-alkylene-CO, R6Sxe2x80x94C1-4-alkylene-CO, R6SOxe2x80x94C1-4-alkylene-CO, R6SO2xe2x80x94C1-4-alkylene-CO or 2-oxo-morpholino-C1-4-alkylene-CO group, wherein
R4 to R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2 or 2-oxo-morpholino group, where
R4 and R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups,
a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4 or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by the group R6, by an R5xe2x80x94C1-4-alkyl, R5xe2x80x94CO, R5xe2x80x94C1-4-alkylene-CO, (R4NR6)xe2x80x94C1-4-alkylene-CO, R6Oxe2x80x94C1-4-alkylene-CO, R6Sxe2x80x94C1-4-alkylene-CO, R6SOxe2x80x94C1-4-alkylene-CO, R6SO2xe2x80x94C1-4-alkylene-CO or 2-oxo-morpholino-C1-4-alkylene-CO group, wherein
R4 to R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups,
a pyrrolidin-3-yl-NR4, piperidin-3-yl-NR4 or piperidin-4-yl-NR4 group substituted in each case at the cyclic nitrogen atom by a C2-4-alkyl group, wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2 or 2-oxo-morpholino group, where
R4 and R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups,
a R5xe2x80x94C1-4-alkylene-NR4 group wherein R4 and R5 are as hereinbefore defined, or
a C2-4-alkyl-NR4 group wherein the C2-4-alkyl moiety is substituted in each case from position 2 by an (R4NR6), R6O, R6S, R6SO, R6SO2 or 2-oxo-morpholino group, where
R4 and R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups,
a 2-oxo-morpholin-4-yl group substituted by the group R7 or by the group R7 and a C1-4-alkyl group, where
R7 represents a C3-4-alkyl, hydroxy-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, di-(C1-4-alkyl)-amino-C1-4-alkyl, pyrrolidino-C1-4-alkyl, piperidino-C1-4-alkyl, morpholino-C1-4-alkyl, 4-(C1-4-alkyl)-piperazino-C1-4-alkyl, C1-4-alkylsulphanyl-C1-4-alkyl, C1-4-alkylsulphinyl-C1-4-alkyl, C1-4-alkylsulphonyl-C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxycarbonyl-C1-4-alkyl, aminocarbonyl-C1-4-alkyl, C1-4-alkyl-aminocarbonyl-C1-4-alkyl, di-(C1-4-alkyl)-aminocarbonyl-C1-4-alkyl, pyrrolidinocarbonyl-C1-4-alkyl, piperidinocarbonyl-C1-4-alkyl, morpholinocarbonyl-C1-4-alkyl or a 4-(C1-4-alkyl)-piperazinocarbonyl-C1-4-alkyl group,
a 2-oxo-morpholin-4-yl group substituted by two groups R7, where R7 is as hereinbefore defined and the two groups R7 may be identical or different,
a 2-oxo-morpholin-4-yl group wherein the two hydrogen atoms of a methylene group are replaced by a xe2x80x94(CH2)m, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2xe2x80x94CH2, xe2x80x94CH2CH2xe2x80x94Yxe2x80x94CH2CH2 or xe2x80x94CH2CH2xe2x80x94Yxe2x80x94CH2CH2CH2xe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups, where
Y is as hereinbefore defined and
m represents the number 2, 3, 4, 5 or 6,
a 2-oxo-morpholin-4-yl group wherein a hydrogen atom in the 5 position together with a hydrogen atom in the 6 position is replaced by a xe2x80x94(CH2)n, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2CH2 or xe2x80x94CH2xe2x80x94C2xe2x80x94Yxe2x80x94CH2xe2x80x94 bridge, where
Y is as hereinbefore defined and n denotes the number 2, 3 or 4,
or, if C together with D represents a group Re, it may also represent a 2-oxo-morpholin-4-yl group which may be substituted by 1 to 4 C1-2-alkyl groups,
C denotes an xe2x80x94Oxe2x80x94C1-6-alkylene group, where the alkylene moiety is linked to the group D, or an oxygen atom, while this may not be linked to a nitrogen atom of the group D, and
D denotes an amino group substituted by 2 C1-4-alkyl groups wherein the alkyl groups may be identical or different and each alkyl moiety may be substituted from position 2 by a C1-4-alkoxy or di-(C1-4-alkyl)-amino group or by a 4- to 7-membered alkyleneimino group, while in the abovementioned 6- to 7-membered alkyleneimino groups a methylene group in each case may be replaced in the 4 position by an oxygen or sulphur atom or by a sulphinyl, sulphonyl or Nxe2x80x94(C1-4-alkyl)-imino group,
a 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4 methyl groups,
a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2 methyl groups where in each case a methylene group in the 4 position is replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl or Nxe2x80x94(C1-4-alkyl)-imino group,
an imidazolyl group optionally substituted by 1 to 3 methyl groups,
a C5-7-cycloalkyl group wherein a methylene group is replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl or Nxe2x80x94(C1-4-alkyl)-imino group, or
C together with D denotes a hydrogen atom,
a C1-6-alkoxy group optionally substituted from position 2 by a hydroxy or C1-4-alkoxy group,
a C3-7-cycloalkoxy or C3-7-cycloalkyl-C1-4-alkoxy group,
a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,
or a group Re, where
Re denotes a C2-6-alkoxy group which is substituted from position 2 by a C4-7-cycloalkoxy or C3-7-cycloalkyl-C1-3-alkoxy group,
a C4-7-cycloalkoxy or C3-7-cycloalkyl-C1-6-alkoxy group, wherein the cycloalkyl moiety is substituted in each case by a C1-4-alkyl, C1-4-alkoxy, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, Nxe2x80x94(C1-2-alkyl)-piperazino, C1-4-alkoxy-C1-2-alkyl, di-(C1-4-alkyl)-amino-C1-2-alkyl, pyrrolidino-C1-2-alkyl, piperidino-C1-2-alkyl, morpholino-C1-2-alkyl, piperazino-C1-2-alkyl or Nxe2x80x94(C1-2-alkyl)-piperazino-C1-2-alkyl group, where the abovementioned cycloalkyl moieties may additionally be substituted by a methyl or ethyl group,
while, unless stated otherwise, the aryl moieties mentioned in the definition of the abovementioned groups denote a phenyl group which may be mono- or disubstituted by Rxe2x80x2, while the substituents may be identical or different, and
Rxe2x80x2 represents a fluorine, chlorine, bromine or iodine atom, a C1-2-alkyl, trifluoromethyl or C1-2-alkoxy group, or
two groups Rxe2x80x2, if they are bound to adjacent carbon atoms, together denote a C3-4-alkylene, methylenedioxy or 1,3-butadien-1,4-ylene group.
Preferred compounds of the above general formula I are those wherein
X denotes a nitrogen atom,
Ra denotes a hydrogen atom,
Rb denotes a 1-phenylethyl, 3-methylphenyl, 3-chlorophenyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,
Rc denotes an xe2x80x94Axe2x80x94B group wherein
A denotes a xe2x80x94OCH2CH2, xe2x80x94OCH2CH2CH2 or xe2x80x94OCH2CH2CH2CH2 group, where the alkylene moiety in each case is linked to the group B, and
B denotes a piperidino group wherein the two hydrogen atoms in the 4 position are replaced by a xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CO, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NCH3xe2x80x94CH2 or xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 bridge,
a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94CH2 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94 bridge, where in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring,
a piperidino group which is substituted in the 4 position by a 2-oxo-morpholino or 2-oxo-morpholino methyl group, where the 2-oxo-morpholino moiety may be substituted in each case by one or two methyl groups,
a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group,
a piperidino group which is substituted in the 4 position by an R6S group, where
R6 denotes a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group,
a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuranylmethyl or 2-oxo-tetrahydrofuranylcarbonyl group,
a piperazino group which is substituted in the 4 position by a [2-(2-oxo-tetrahydrofuran-3-ylsulphenyl)ethyl] group,
a piperidin-4-yl group which is substituted in the 1 position by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group,
a 2-oxo-morpholin-4-yl group which is substituted by a methoxymethyl or methoxyethyl group,
a 2-oxo-morpholin-4-yl group wherein the two hydrogen atoms of a methylene group are replaced by a xe2x80x94CH2CH2CH2CH2, xe2x80x94CH2CH2CH2CH2CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2 or xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2CH2xe2x80x94 bridge,
and Rd represents a methoxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,
the tautomers, stereoisomers and the salts thereof.
Other preferred compounds of the above general formula I are those wherein
X denotes a nitrogen atom,
Ra denotes a hydrogen atom,
Rb denotes a 1-phenylethyl, 3-methylphenyl, 3-chlorophenyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,
Rc denotes a methoxy, cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group and
Rd denotes an xe2x80x94Axe2x80x94B group wherein
A denotes an xe2x80x94OCH2CH2, xe2x80x94OCH2CH2CH2 or xe2x80x94OCH2CH2CH2CH2 group, where the alkylene moiety in each case is linked to the group B, and
B denotes a piperidino group wherein the two hydrogen atoms in the 4 position are replaced by a xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CO, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2, xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94NCH3xe2x80x94CH2 or xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 bridge,
a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position are replaced by a xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94CH2 or xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94 bridge, where in each case the left-hand end of the abovementioned bridges is bound to the 3 position of the piperazino ring,
a piperidino group which is substituted in the 4 position by a 2-oxo-morpholino or 2-oxo-morpholino methyl group, while the 2-oxo-morpholino moiety may be substituted in each case by one or two methyl groups,
a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group,
a piperidino group which is substituted in the 4 position by an R6S group, where
R6 represents a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group,
a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuranylmethyl or 2-oxo-tetrahydrofuranylcarbonyl group,
a piperazino group which is substituted in the 4 position by a [2-(2-oxo-tetrahydrofuran-3-ylsulphenyl)ethyl] group,
a piperidin-4-yl group which is substituted in the 1 position by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group,
a 2-oxo-morpholin-4-yl group which is substituted by a methoxymethyl or methoxyethyl group,
a 2-oxo-morpholin-4-yl group wherein the two hydrogen atoms of a methylene group are replaced by a xe2x80x94CH2CH2CH2CH2, xe2x80x94CH2CH2CH2CH2CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2 or xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2CH2xe2x80x94 bridge,
the tautomers, stereoisomers and the salts thereof.
Most particularly preferred compounds of the above general formula I are those wherein
X denotes a nitrogen atom,
Ra denotes a hydrogen atom,
Rb denotes a 3-chloro-4-fluorophenyl group,
Rc denotes a cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuran-2-yl-methoxy group and
Rd denotes an xe2x80x94Axe2x80x94B group wherein
A denotes a xe2x80x94OCH2CH2 group, where the alkylene moiety is linked to the group B, and
B denotes a piperazino group wherein a hydrogen atom in the 3 position together with the hydrogen atom in the 4 position is replaced by a xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94 bridge, while the left-hand end of the abovementioned bridge is bound to the 3 position of the piperazino ring,
a piperazino group which is substituted in the 4 position by a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran-4-yl-,2-oxo-tetrahydrofuranylmethyl or 2-oxo-tetrahydrofuranylcarbonyl group,
the tautomers, stereoisomers and the salts thereof.
The following are mentioned as examples of particularly preferred compounds:
(1) 4-[(3-chloro-4-fluorophenyl) amino]-6-cyclopentylmethoxy-7-{2-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-quinazoline,
(2) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-{2-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-quinazoline,
(3) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-{2-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-quinazoline and
(4) 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(2-{4-[(R)-(2-oxo-tetrahydrofuran-5-yl)methyl]-piperazin-1-yl}-ethoxy)-quinazoline,
the tautomers, stereoisomers and the salts thereof.
The compounds of general formula I may be prepared by the following methods, for example:
a) reacting a compound of general formula 
optionally formed in the reaction mixture
wherein
Ra, Rb and X are as hereinbefore defined,
one of the groups Rcxe2x80x2 or Rdxe2x80x2 denotes a xe2x80x94Cxe2x80x94D group as mentioned hereinbefore for Rc or Rd and
the other group Rcxe2x80x2 or Rdxe2x80x2 denotes an xe2x80x94Axe2x80x2xe2x80x94Z1 group, where
Axe2x80x2 denotes a C1-6-alkylene or xe2x80x94Oxe2x80x94C1-6-alkylene group and
Z1 denotes an exchangeable group such as a halogen atom or a substituted sulphinyl or sulphonyl group, e.g. a chlorine or bromine atom, a methylsulphinyl, propylsulphinyl, phenylsulphinyl, benzylsulphinyl, methylsulphonyl, propylsulphonyl, phenylsulphonyl or benzylsulphonyl group,
with a compound of general formula:
Hxe2x80x94Gxe2x80x83xe2x80x83,(III)
wherein
G represents one of the groups mentioned for B hereinbefore, which is linked to the group A via a nitrogen atom.
The reaction is expediently carried out in a solvent such as acetonitrile, tetrahydrofuran, dioxan, toluene, chlorobenzene, dimethylformamide, dimethylsulphoxide, methylene chloride, ethylene glycol diethyl ether or sulpholane, optionally in the presence of an inorganic or tertiary organic base, e.g. sodium carbonate or potassium hydroxide, a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (Hxc3xcnig base), whilst these organic bases may simultaneously also serve as solvent, and optionally in the presence of a reaction accelerator such as an alkali metal iodide at temperatures between xe2x88x9220 and 150xc2x0 C., but preferably at temperatures between xe2x88x9210 and 100xc2x0 C. The reaction may, however, also be carried out without a solvent or in an excess of the compound of general formula III used.
b. In order to prepare a compound of general formula I wherein one of the groups Rc or Rd represents a xe2x80x94Axe2x80x94Bxe2x80x2 group where A is as hereinbefore defined and Bxe2x80x2 represents one of the groups mentioned for B hereinbefore which contains an imino or HNR4 group substituted by R6 or by an R5xe2x80x94C1-4-alkyl group, where R4 to R6 are as hereinbefore defined: reacting a compound of general formula: 
wherein
Ra, Rb and X are as hereinbefore defined,
one of the groups Rcxe2x80x3 or Rdxe2x80x3 denotes a xe2x80x94Cxe2x80x94D group mentioned above for Rc or Rd and
the other group Rcxe2x80x3 or Rdxe2x80x3 denotes an xe2x80x94Axe2x80x94Bxe2x80x3 group, where
A, C and D are as hereinbefore defined and
Bxe2x80x3 represents a group which can be converted by alkylation into a group Bxe2x80x2, where Bxe2x80x2 represents one of the groups mentioned for B hereinbefore which contains an imino or HNR4 group substituted by R6 or by an R5xe2x80x94C1-4-alkyl group, where Ra to Ra are as hereinbefore defined,
with a compound of general formula:
xe2x80x83Z2xe2x80x94Uxe2x80x83xe2x80x83,(V)
wherein
U denotes the group R6 or a R5xe2x80x94C1-4-alkyl group, where R5 and R6 are as hereinbefore defined, and
Z2 denotes an exchangeable group such as a halogen atom or a substituted sulphonyloxy group, e.g. a chlorine or bromine atom, a methylsulphonyloxy, propylsulphonyloxy, phenylsulphonyloxy or benzylsulphonyloxy group, or
Z2 together with an adjacent hydrogen atom denotes another carbon-carbon bond which is linked to a carbonyl group.
The reaction is expediently carried out in a solvent such as methanol, ethanol, isopropanol, acetonitrile or dimethylformamide and optionally in the presence of a base such as tri-ethylamine, N-ethyl-diisopropylamine or potassium carbonate at temperatures between 0 and 150xc2x0 C., but preferably at temperatures between 20 and 100xc2x0 C.
If in a compound of general formula V Z2 denotes an exchangeable group, the reaction is preferably carried out in a solvent or mixture of solvents such as acetonitrile, methylene chloride, dimethylformamide, dimethyl sulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, expediently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (Hxc3xcnig base), while these organic bases may simultaneously also serve as solvent, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution, expediently at temperatures between xe2x88x9220 and 200xc2x0 C., preferably at temperatures between 0 and 150xc2x0 C., or
if in a compound of general formula V Z2 together with an adjacent hydrogen atom denotes another carbon-carbon bond which is linked to a carbonyl group, the reaction is preferably carried out in a solvent such as methanol, ethanol, isopropanol or acetonitrile at temperatures between 0 and 100xc2x0 C., but preferably at temperatures between 20xc2x0 C. and the boiling temperature of the reaction mixture.
c. In order to prepare a compound of general formula I wherein one of the groups Rc or Rd denotes an xe2x80x94Axe2x80x94Bxe2x80x2 group, where A is as hereinbefore defined and Bxe2x80x2 represents one of the groups mentioned for B hereinbefore which contains an imino or HNR4 group substituted by an R5CO, R5xe2x80x94C1-4-alkylene-CO, (R4NR6)xe2x80x94C1-4-alkylene-CO, R6Oxe2x80x94C1-4-alkylene-CO, R6Sxe2x80x94C1-4-alkylene-CO, R6SOxe2x80x94C1-4-alkylene-CO, R6SO2xe2x80x94C1-4-alkylene-CO or 2-oxo-morpholino -C1-4-alkylene-CO group, where R4 to R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups:
reacting a compound of general formula: 
wherein
Ra, Rb and X are as hereinbefore defined,
one of the groups Rcxe2x80x3 or Rdxe2x80x3 denotes a xe2x80x94Cxe2x80x94D group mentioned for Rc or Rd hereinbefore and
the other group Rcxe2x80x3 or Rdxe2x80x3 denotes an xe2x80x94Axe2x80x94Bxe2x80x3 group, where
A, C and D are as hereinbefore defined and
Bxe2x80x3 represents a group which can be converted by acylation into a group Bxe2x80x2, where Bxe2x80x2 represents one of the groups mentioned for B hereinbefore which contains an imino or
HNR4 group substituted by an R5CO, R5xe2x80x94C1-4-alkylene-CO, (R4NR6)xe2x80x94C1-4-alkylene-CO, R6Oxe2x80x94C1-4-alkylene-CO, R6Sxe2x80x94C1-4-alkylene-CO, R6SOxe2x80x94C1-4-alkylene-CO, R6SO2xe2x80x94C1-4-alkylene-CO or 2-oxo-morpholino-C1-4-alkylene-CO group, where R4 to R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups,
with a compound of general formula:
HOxe2x80x94COxe2x80x94Wxe2x80x83xe2x80x83,(VI)
wherein
W represents the group R5 or an R5xe2x80x94C1-4-alkyl, (R4NR6)xe2x80x94C1-4-alkyl, R6Oxe2x80x94C1-4-alkyl, R6Sxe2x80x94C1-4-alkyl, R6SOxe2x80x94C1-4-alkyl, R6SO2xe2x80x94C1-4-alkyl or 2-oxo-morpholino-C1-4-alkyl group, wherein R4 to R6 are as hereinbefore defined and the 2-oxo-morpholino moiety may be substituted by one or two C1-2-alkyl groups.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran or dioxan, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexyl-carbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-carbonyldiimidazole, triphenyl-phosphine/carbon tetrachloride or O-(benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium-tetrafluoroborate or with a corresponding reactive derivative such as a corresponding ester, acid halide or anhydride, optionally with the addition of an inorganic or organic base, preferably with the addition of an organic base such as triethylamine, N-ethyl-diisopropylamine or 4-dimethylamino-pyridine, expediently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 80xc2x0 C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, and
protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy-benzyl or 2,4-dimethoxybenzyl group, and additionally phthalyl, for the amino group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120xc2x0 C., preferably at temperatures between 10 and 100xc2x0 C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100xc2x0 C., but preferably at ambient temperatures between 20 and 60xc2x0 C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxan, methanol or diethyl ether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120xc2x0 C. or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50xc2x0 C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxan, at temperatures between 20 and 50xc2x0 C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (xe2x88x92)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (xe2x88x92)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
The compounds of general formulae II to VI used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf. Examples I to XIV).
As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerisation or tyrosine kinase itself. It is also possible that the transmission of signals to components located further down is blocked.
The biological properties of the new compounds were investigated as follows:
The inhibition of the EGF-R-mediated signal transmission can be demonstrated e.g. with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha. A cell line of murine origin dependent on interleukin-3-(IL-3) which was genetically modified to express functional human EGF-R was used here. The proliferation of these cells known as F/L-HERc can therefore be stimulated either by murine IL-3 or by EGF (cf. von Rxc3xcden, T. et al. in EMBO J. 7, 2749-2756 (1988). and Pierce, J. H. et al. in Science 239, 628-631 (1988)).
The starting material used for the F/L-HERc cells was the cell line FDC-P1, the production of which has been described by Dexter, T. M. et al. in J. Exp. Med. 152, 1036-1047 (1980). Alternatively, however, other growth-factor-dependent cells may also be used (cf. for example Pierce, J. H. et al. in Science 239, 628-631 (1988), Shibuya, H. et al. in Cell 70, 57-67 (1992) and Alexander, W. S. et al. in EMBO J. 10, 3683-3691 (1991)). For expressing the human EGF-R cDNA (cf. Ullrich, A. et al. in Nature 309, 418-425 (1984)) recombinant retroviruses were used as described by von Rxc3xcden, T. et al., EMBO J. 7, 2749-2756 (1988), except that the retroviral vector LXSN (cf. Miller, A. D. et al. in BioTechniques 7, 980-990 (1989)) was used for the expression of the EGF-R cDNA and the line GP+E86 (cf. Markowitz, D. et al. in J. Virol. 62, 1120-1124 (1988)) was used as the packaging cell.
The test was performed as follows:
F/L-HERc cells were cultivated in RPMI/1640 medium (Bio Whittaker), supplemented with 10% foetal calf serum (FCS, Boehringer Mannheim), 2 mM glutamine (Bio Whittaker), standard antibiotics and 20 ng/ml of human EGF (Promega), at 37xc2x0 C. and 5% CO2. In order to investigate the inhibitory activity of the compounds according to the invention, 1.5xc3x97104 cells per well were cultivated in triplicate in 96-well dishes in the above medium (200 xcexcl), the cell proliferation being stimulated with either EGF (20 ng/ml) or murine IL-3. The IL-3 used was obtained from culture supernatants of the cell line X63/0 mIL-3 (cf. Karasuyama, H. et al. in Eur. J. Immunol. 18, 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethylsulphoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated for 48 hours at 37xc2x0 C.
In order to determine the inhibitory activity of the compounds according to the invention the relative cell number was measured in O.D. units using the Cell Titer 96(trademark) AQueous Non-Radioactive Cell Proliferation Assay (Promega). The relative cell number was calculated as a percentage of the control (F/LHERc cells without inhibitor) and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC50) was derived therefrom. The following results were obtained:
The compounds of general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases. These are e.g. benign or malignant tumours, particularly tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
The compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosine kinases, e.g. in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, xcex11-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
The compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in chronic inflammatory changes such as cholecystitis, Crohn""s disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Mxc3xa9nxc3xa9trier""s disease, secreting adenomas and protein loss syndrome, and also for treating nasal polyps and polyps of the gastrointestinal tract of various origins such as villous or adenomatous polyps of the large intestine, but also polyps in familial polyposis coli, in intestinal polyps in Gardner""s syndrome, in polyps throughout the entire gastro-intestinal tract in Peutz-Jeghers Syndrome, in inflammatory pseudopolyps, in juvenile polyps, in colitis cystica profunda and in pneumatosis cystoides intestinales.
In addition, the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat kidney diseases, particularly in cystic changes as in cystic kidneys, for treating renal cysts which may be idiopathic in origin or occur in syndromes such as tubercular sclerosis, in von Hippel-Lindau syndrome, in nephrophthisis and spongy kidney and other diseases caused by abnormal function of tyrosine kinases, such as e.g. epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of haematopoietic cells, etc.
By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastine), compounds which interact with nucleic acids (e.g. cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), antibodies, etc. For treating respiratory tract diseases, these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic, broncholytic and/or anti-inflammatory activity. For treating diseases in the region of the gastrointestinal tract, these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion, or anti-inflammatory substances. These combinations may be administered either simultaneously or sequentially.
These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation.
For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.
The following Examples are intended to illustrate the present invention without restricting it:
Preparation of the Starting Compounds: